Method for combatting harmful microorganisms

ABSTRACT

The present invention provides a method for combating harmful microorganisms, which comprises applying to a desired site an effective amount of 2-hydroxy-benzophenone of the formula WHEREIN Z1 denotes halogen or alkyl, X1 and Y1 each denote hydrogen, halogen, alkyl, cycloalkyl, benzene or substituted benzene, X2, X3, X4, Y2 and Y3 each denote hydrogen, halogen or alkyl and X5 denotes hydrogen or halogen, with the number of the alkyl, benzene and cyclohexyl radicals as substituents being together at most 4. The anti-bacterial range of these 2-hydroxy benzophenones extends both to gram-positive and gram-negative bacteria.

Unite States Patent 1 Duennenberger et al.

1 1 Dec. 2, 1975 METHOD FOR COMBATTING HARMFUL MHCROORGANISMS [75]lnventors: Max Duennenberger, Frenkendorf; Max Schellenbaum, Muttenz,both of Switzerland [73] Assignee: Ciba-Geigy AG, Basel, Switzerland[22] Filed: Apr. 16, 1973 211 Appl. No.: 352,379

Related US. Application Data [62] Division of Ser. No. 53,026, July 7,1970, abandoned.

[30] Foreign Application Priority Data July 17, 1969 Switzerland10936/69 [52] U.S. Cl. 424/331; 162/161; 252/8.6; 252/106; 260/591 [51]Int. Cl. A61L 13/00; DO6M 13/12 [58] Field of Search 424/331; 260/591;117/138.5; 162/161; 252/8.6, 106

[56] References Cited UNITED STATES PATENTS 4/1947 Houtman 260/59111/1949 Meyer 260/591 X OTHER PUBLICATIONS Chem. Abs, Vol. 67, 1967,89834d.

Chem. Abs, Vol.47, 1953, 23586.

Primary ExaminerWilliam E. Schulz [57] ABSTRACT The present inventionprovides a method for combating harmful microorganisms, which comprisesapplying to a desired site an effective amount of 2-hydroxybenzophenoneof the formula wherein Z denotes halogen or alkyl, X and Y each 6Claims, N0 Drawings METHOD FOR COMBA'ITING HARMFUL MICROORGANISMS Thisis a division of application Ser. No. 53,026, filed on July 7, 1970, andnow abandoned.

The subject of the present invention is the use of 2-hydroxybenzophenones of formula wherein Z denotes a halogen atom or analkyl group, X, and Y each denote a hydrogen or halogen atom or an alkylor cyclohexyl radical or optionally substituted benzene radical, X X X Yand Y each denote a hydrogen or halogen atom or an alkyl group and Xdenotes a hydrogen or halogen atom, with the number of the alkyl,benzene and cyclohexyl radicals as substituents together being at most4, for combatting harmful micro-organisms.

Amongst the compounds of formula (1), those in which at least 2 of the Xand y radicals represent hydrogen atoms, are preferred.

At the same time, compounds of formula wherein Z denotes a halogen atomor an alkylgroup with l to 4 carbon atoms, X X X X Y Y and Y each denotean alkyl group with l to 4 carbon atoms or a hydrogen or halogen atom,and X each denotes a hydrogen or halogen atom, with the number of alkylgroups being at most 4, are above all of interest.

Possible halogen atoms for the substituents in formulae (l) and (2) areiodine and above all chlorine and bromine. Possible alkyl groups forthe. substituents in formulae (1) and (2) are above all straight-chainradicals, for example ethyl, n-propyl or n-butyl radicals, but

preferably methyl radicals.

C II '-Y7 Compounds of formula wherein Z denotes an alkyl group with atmost 2 carbon atoms or a chlorine or bromine atom, X X X Y and Y eachdenote an alkyl group with at most 2 carbon atoms or a hydrogen,chlorineor bromine atom, and X denotes a hydrogen, chlorine or bromine atom,

2 with the number of the alkyl groups being at most 3, should behighlighted.

Amongst the compounds of formulae (2) or (3), those in which at least 3,or 2, of the X and Y radicals, 5 preferably the X radicals, representhydrogen atoms and the number of alkyl groups is at most 2 arepreferred.

Special interest attaches to the 2-hydroxybenzophenones of formula 10 Inthe forefront of practical interest is the use of 2-hydroxybenzophenones of formula wherein X and X each denote a methylgroup or a hydrogen or chlorine atom.

Particularly suitable 2-hydroxybenzophenones correspond to the formulawherein X and X have the indicated significance and n is l or 2.

Individual specially important 2-hydroxybenzophenones possess theformulae:

and

Cl Cl. C].

The 2-hydroxybenzophenones of formulae (1) to (8) are known or aremanufactured according to methods which are in themselves known, forexample from the corresponding phenylbenzoates by the Fries reaction(compare Baltzly et al. Journal of the American Chemical Society 77,2522" or LP. and M. Fieser, Lehrbuch der organischen Chemie (Textbook ofOrganic Chemistry) 1954, page 728). The reaction can be carried out inthe melt or in the presence of an organic solvent, for examplenitrobenzene. On heating the corresponding phenylbenzoate together withaluminium chloride, the 2-hydroxybenzophenones of formula (l) are thenproduced.

2-Hydroxybenzophenones of formula (1) are obtained by rearrangement ofan ester of formula wherein X to X Z and Y,, Y and Y have the indicatedsignificance and the position marked (a) has to be unsubstituted.

The starting products of formula (9) are obtained according to knownmethods, for example by reaction of an appropriate benzoyl halide withan appropriate phenol.

A particularly surprising feature of the compounds of formula (1) is thebroad anti-bacterial range of action, which in some of these compoundsextends both to gram-positive and to gram-negative bacteria. Here thelack of odour and lack of colour of the compounds of formula (1) is ofparticular value with regard to the technical aspects of their use.

The present invention also comprises the use of the compounds of formula(1) in combatting pests quite generally. The use of the anti-microbialcompounds is possible on a very broad basis, especially for protectingorganic substrates against attack by destructive and pathogenic (alsophytopathogenic micro-organisms. Accordingly, the anti-microbial agentsmentioned are suitable for use both as preservatives and asdisinfectants for technical products of all kinds, in plant protection,in agriculture, in veterinary medicine and in cosmetics.

The 2-hydroxybenzophenones of formula (1) are thus used for finishing orprotecting organic material, especially textiles, by incorporating atleast one of these compounds into the organic materials to be finishedor to be protected or applying such a compound to the surface of thematerials.

Amongst the non-textile technical products which can be preserved withthe aid of the compounds of formula (l), the following may be selectedas examples:

glues, adhesives, paints, textile auxiliary agents or finishing agents,dyeing pastes or printing pastes and similar preparations based onorganic and inorganic dyestuffs or pigments, also including those whichcontain casein or other organic compounds as admixtures. Wall andceiling paints, for example those containing a colour binder whichcontains albumen, are also protected against attack by pests by anaddition of the compounds of formula (1). The compounds can also be usedfor protecting timber.

The compounds of formula (1) can also be used as preservatives in thecellulose and paper industry, for example for preventing the knownformation of slime, caused by micro-organisms, in the apparatuses usedfor the production of paper.

Furthermore, detergents and cleansing agents having an excellentanti-bacterial and/or anti-micotic action are obtained by combination ofthe compounds of formula (l) with surface-active substances, especiallydetergent substances. The compounds of formula (1 can for example beincorporated into soaps or be combined with soap-free detergent or othersurface-active substances, especially also non-ionic, detergents (e.g.condensation products of alkyl phenols with ethylene oxide orpolyethylene glycols) an ionic detergents (e.g. alkyl aryl sulphonates,fatty alcohol sulphonates or alkyl sulphonates), or cationic detergents(e.g. higher alkyl dimethyl benzyl ammonium halides, or higher alkyltrimethyl ammonium halides), or can be combined with mixtures of soapsand soap-free detergent substances, with their anti-microbial activityremaining fully preserved in these combinations. Using aqueouspreparations of such detergents and cleansing agents, which containcompounds of formula (1), it is for example possible to impart ananti-microbial finish to textile materials on washing, since the activesubstance can be substantively absorbed on to the textile material.

Cleansing agents which contain the compounds of the abovementionedformula can also be employed in industry and household, as well as inthe foodstuff trade, for example dairies, breweries and abbattoirs. Thepresent compounds can also be used as a constituent of preparationswhich are used for cleansing and disinfecting purposes.

The action of the compounds of formula (1) can also be utilised in thepreservative and disinfectant finishes of plastics. When usingplasticisers it is advantageous to add the anti-microbial additive tothe plastic dissolved or dispersed in the plasticiser. Appropriately, asuniform a distribution in the plastic as possible should be ensured. Theplastics with anti-microbial properties can be employed for utensils ofall kinds in which an activity against the most diverse germs, such asfor example bacteria and fungi, is desired, such as, for example, indoormats, bathroom curtains, toilet seats, foot grids in swimming baths,wall coverings and the like. Floor polishes and furniture polisheshaving a disinfectant action are obtained by their incorporation inappropriate wax and polishing compositions.

The compounds of formula (1 can furthermore be used for the preservativeand disinfectant finishing of fibres and textiles, in which case theycan be applied to natural and synthetic fibres and there display alasting action against harmful (including pathogenic) microorganisms,for example fungi and bacteria. Here the compounds can be added before,simultaneously with, or after a treatment of these textiles with othersubstances, for example dyeing or printing pastes, finishes and thelike.

Textiles treated in this way also show a protection against theoccurrence of the odour of perspiration such as is occasioned bymicro-organisms.

is formed practically quantitatively with elimination of hydrogenchloride (melting point 128 to 129C). 28 g of aluminium chloride areadded over the course of 10 The anti-microbial active substances can beapplied 5 minutes at 140 to 150C without isolation of the ester. to thetextile materials to be protected in the most di- The mixture is stirredfor a further 30 minutes at 150 verse manner, for example byimpregnation or spraying to 160C and 100 cm of chlorobenzene arethereafter with solut1ons or suspensions which contain the aboveadded.The solution is poured out onto ice and the mixmentloned compounds as anactive substance. The acture is subjected to a steam distillation. Theproduct is t1ve substance content can, depending on the end use, 10filtered off and dried in vacuo at 60C. Yield: 30 g of lie between 0.1and 50 g, preferably between 1 and 30 light yellow crystals ofmelting'point 1 18 to 124C. g, of active substance per litre oftreatment liquid. After three rec1ystallisations from cyclohexane, the

In most cases, textile materials of both synthetic or product I offormula natural origin are sufficiently protected against fungal 0 OHand bacterial attack by a content of 0.1 to 3% of active 91 n substance.The active substances mentioned can op- (11) tionally be employedconjointly with other textile auxiliary agents, such as finishingagents, creaseproofing 1 C1 01. agents and the like.

The use forms of the active substances according to 20 is obtained inthe form of colourless crystals. Melting the invention can correspond tothe customary formupoint: 138 to 139C. As a by-product, the product oflations of pesticides; for example, agents which contain formula thesaid active substances can optionally also contain 0 cl furtheradditives such as solvents,'dispersing agents, 01 n wetting agents oradhesives (e.g. an alkali metal salt of carboxy methylcellulose,methylcellulose or polyacryl (l2) amide, and the like, as well as otherpesticides. In par- 01 Cl 03 ticular, however, the agents can alsofurthermore contain a solid or liquid diluent or a solid or liquidcarrier in addition to the active substance of formula (1). can beisolated in the mother liquor. Melting point:

The active substance content of these agents can lie 180 to 181C.between 0.1 and 50 g, preferably between 1 and 30 g, The compounds 11 toXXXI of formula of active substance per 1000 g of agent.

EXAMPLE 1 20.9 g of 3,4-dichlorobenzoyl chloride and 16.3 g of3,5-dichlorophenol are stirred for one hour at 150C under a stream ofnitrogen, in the course of which the (13) product of formula 0 c1 11 01no) n-( -O--q G1 G1 are manufactured in a similar manner to compound I:

Table A C0m- R R2 R R4 R5 R6 R1 R; R9 Meltin; point pound 1 C1 H Cl H HC1 C] H H 138- 139 11 CH C1 CH3 H H H C1 H C1 103 104 111 CH, H CH H H HC1 H Cl 94 1v Cl H H C1 H H Cl H C1 115-116 v C1 H C1 H H H C1 H H161-162 v1 C1 C1 H C1 H H C1 H H 176 177 v11 C1 C1 H C1 H C1 C1 H H 2172l8 VIII C1 C1 H C1 Cl H C1 H H 81 82 1X C1 C1 H C1 H H CH H H 141 142.5x C1 C1 H C1 H H H H H 143 144 x1 C1 c1 H C1 H H Br H H 185 186 x11 C1C1 H C1 CH H H H H 125 126 x111 C1 C1 H Cl H CH CH H H 163 164 x1v c1 0H 01 cH H cH, H H 103 104 XV CH C1 CH H H H H H H 203 204 xv! CH C1 CH HCl H H H H 91- 92 xv11 CH H CH H H H Cl H H 132 133 xv111 CH H CH3 H H H131 H H 147 148 x1x c1 H C1 H H H H H H 156-157 xx Cl H C1 H Cl H C1 H H106 XX] Cl H C1 H H H Br H H 157 -158 Xxn Cl H Cl H H H CH, H H 177 178xx111 01 H 01 H CH H H H H 117 -11s xx1v c1 H C1 H C1 H H C1 H 107 10sxxv C1 H Cl H Cl H H H C1 -111 XXVI C1 H C1 H C1 H H H H 72 73 TableA-continued Com- R R2 R3 R4 R, R R, R R9 Melting point pound XXVII Cl C1H c1 c1 H H H H 94 95 XVIII CH c1 H H Cl H H C! H 122 123 XXIX CH Cl CHCI H C! Cl H H 136 137 XXX CH c1 CH Cl Cl H Cl H H 129 130 XXXI CH C1CH3 c1 Cl H H H 96 97 EXAMPLE 2 Determination of the minimum inhibitoryTable Coominued concentration (MIC) against bacteria and fungi in thegradient plate test l)+ 2)l-+- Minimum inhibitory concentrations againstEscherichia coli (bacteriostasis) The compounds of formula (l3), insuitable formula- MIC f ppm tions (for example as solutions indimethylsulphoxide) V 25 of a certain concentration, are mixed with warmbrain Q? :8 heart infusion agar (bacteria) or mycophil agar (fungi) 20xx 10 respectively. The liquid mixtures are cast onto a solidi g fiedwedge-shaped base agar layer and also allowed to xxm solidify. XXIV v 201 w. Szybalski et al., Science 116, 26 1952 I f 2)++ Nuesch and Knuesel,Sideromycins, in the book by Gottlieb and Shaw, Antibiotics, Mechanismof Action, Vol. 1 (1967), Springer Verlag. Table D The test organlstnsare now applied In a hne fight Minimum inhibitory concentrations againstTrichophyton angles to the gradlent by means of a Pasteur pipette.mentagrophytes (fungistasis) After an incubation of 24 hours at 37C(bacteria) or f ppm 72 hours at 30C (fungi) respectively, the length ofthe I v "0.3 germs which have grown on the inoculation stroke is g imeasured and expressed in ppm of active substance. v 10 The results aregiven in Table B to E below. 3

Table B 1 1x 1 10 Minimum inhibitory concentrations againstStaphylococcus x 1o aureus (bacteriostasis) XI 4 Compound MIC in ppm X"1 XIII 10 I I 0.2 XIv a 5 II 2 40 XVI 3 III 20 XvII 4 1v 4 XvIII 4 v 2.5XIX 5 v1 4 XX 1 VII 18 XXI 1 VIII 4 XXII 10 IX 20 XXIII 30 x 10 XXIV 2X1 2 XXV 2 XII l0 XXVI 3 XIII 10 XXvII 10 XIv 7 XXvIII 3 xv 25 5O XXIX 1XvI '5 XXX 1 XVII 25 XXXI l xvIII 30 XIX 10 XX 1 i1 7 Table E XXIII 4 tA 0.6 InIrnum In l itory concentrauons agams spergl US fllgfil XXV(fungistasis) XXVI 4 Compound MIC 1n ppm XXvII 4 l 6 xxvIII 4 v v 20xxlx 0.8 Ix 40 xxx 2.5 a X 30 XXXI 4 x 60 XII 50 XVII 35 XVIII 40 XIX 15Table C xx 30 Minimum inhibitory concentrations against Escherichia coliXXI (bacteriostasis) MIC In In Compound Pp XXVI 30 I 20 XXVI! 40 TableE-continued Minimum inhibitory concentrations against Aspergillus nigerEXAMPLE 3 Samples of 100 g of cotton cretonne are impregnated with an0.1% strength solution of compounds of formula (13) in isopropanol at20C on a padder and subsequently squeezed out to leave a 100% liquoruptake.

Samples of 100 g of wool cheviot are also treated in the same manner.

The fabrics dried at 30 to 40C contain 0.1% of active substance relativeto their own weight.

To test the action against bacteria, discs of mm diameter of theimpregnated fabrics, unsoaked and after soaking for 24 hours at 29C, areplaced on brain heart infusion agar plates which are previouslyinoculated with Staphylococcus aureus. The plates are thereafterincubated for 18 hours at 37C.

An assessment is made of, on the one hand, the inhibition zone occurringaround the discs (IZ in mm) and, on the other hand, the microscopicallydetectable growth (G in under and/or on the fabric:

Similar results are also obtained with the other compounds of Table A.

EXAMPLE 4 In order to manufacture an anti-microbial cake of soap, 2.4 gof the compound of formula XX are added to the following mixture: 120 gof base soap in flake form, 0.12 g of the disodium salt ofethylenediaminetetraacetic acid (dihydrate) and 0.24 g of titaniumdioxide.

The soap chips obtained by working the mixture on rolls are powdered bymeans of a rapid-running stirrer and subsequently pressed into a cake ofsoap.

A concentrated aqueous solution of the antimicrobial soap is admixed towarm brain heart infusion agar in such a way that anincorporation-dilution series with 2, 10, and 100 ppm of activesubstance is produced. The warm mixtures are poured into petri dishes,allowed to solidify and subsequently inoculated with Staphylococcusaureus. After 24 hours incubation at 37C the minimum inhibitoryconcentration is determined.

Minimum inhibitory concentration of the antimicrobial soap in ppm ofactive substance: s 2.

Similar results are also obtained with other compounds of Table A.

EXAMPLE 5 The following mixture is worked for 20 minutes at 150C on atwo-roll mill: 100.00 g of polyvinyl chloride, 19.20 g ofdi-(2-ethyl-hexyl)-phthalate, 27.00 g of di-(Z-ethyl-hexyl)-sebacate,1.50 g of Ba/Cd laurate, 0.25 g of stearic acid and 7.80 g of a solutionof 3.10 g of the compounds of formula (13) in 4.70 g of di-(2-ethyl-hexyl )-phthalate.

The roll nip is so adjusted that 1 mm thick hides are produced which aresubsequently pressed for 20 minutes at 165 to 170C under 1400 kg/cm2.

To test the action against bacteria, 10 mm diameter discs are punchedout of the milled plasticised polyvinyl chloride and placed on brainheart infusion agar plates which are previously inoculated withStaphylococcus aureus. The plates are thereafter incubated for 24 hoursat 37C.

An assessment is made of, on the one hand, the inhibition zone occurringaround the discs (IZ in mm) and, on the other hand, the microscopicallydetectable growth (G in under and/or on the plasticised polyvi- V nylchloride.

Table G Compound lZ G No. (mm

l 3 0 XX 2 0 Similar results are also obtained with other compounds ofTable A.

What we claim is:

1. A composition for combatting fungi and bacteria which comprises solidor liquid carrier and an inhibitory amount of a 2-hydroxybenzophenone ofthe formula where Z, denotes an alkyl group with at most 2 carbon atomsor a chlorine or bromine atom, X X X Y and Y each denote an alkyl groupwith at most 2 carbon atoms or a hydrogen, chlorine or bromine atom, andX denotes a hydrogen, chlorine or bromine atom, with the number of thealkyl groups being at most 3.

2. The composition of claim 1, wherein the 2- hydroxy-benzophenone is ofthe formula 3. The composition of claim 1, wherein the 2-hydroxy-benzophenone is of the formula c C l H H O O Cl Cl H Cl 3 c1 c14. The composition of claim 1, wherein the 2- hydroxy-benzophenone is ofthe formula 6. The composition of claim 1, wherein the 2- Cl OHhydroxy-benzophenone is of the formula 15 0 c1 c1 01 H 5. Thecomposition of claim 1, wherein the 2- hydroxy-benzophenone is of theformula

1. A COMPOSITION FOR COMBATTING FUNGI AND BACTERIA WHICH COMPRISES SOLIDOR LIQUID CARRIER AND AN INHIBITORY AMOUNT OF A 2-HYDROXYBENZOPHENONE OFTHE FORMULA
 2. The composition of claim 1, wherein the2-hydroxy-benzophenone is of the formula
 3. The composition of claim 1,wherein the 2-hydroxy-benzophenone is of the formula
 4. The compositionof claim 1, wherein the 2-hydroxy-benzophenone is of the formula
 5. Thecomposition of claim 1, wherein the 2-hydroxy-benzophenone is of theformula
 6. The composition of claim 1, wherein the2-hydroxy-benzophenone is of the formula